This project will place into the hands of many experimental neuroscientists validated, massively-multiplexed tools for recording of neuronal activity, for chemical sensing of neuromodulators, and for highly-patterned optogenetic stimulation with concurrent electrical recording ? in any region of the brain. This will be accomplished by making use of both PIs' decades-long working relationship with microchip foundries, to enable mass production of neural nanoprobes, of VLSI application-specific integrated circuits (?microchips?), and of supporting instrumentation for read-out and control. Our paramount objective in technology development is to optimize usefulness for end- users. We will achieve this by a highly-interactive program that: 1) solicits user needs; 2) assembles and validates neural nanoprobe systems in vivo; 3) deploys complete systems to neuroscientists; 4) provides technical support to enhance the end-users' success with the new neurotechnology; and, subsequently, 5) solicits feedback to enable the design of successive generations of neurotechnology. The technology to be produced and disseminated is based upon the PI's validated neural nanoprobes and advanced, custom microchips for their readout and control. Our existing 256-channel nanoprobe layers modules (assembled into 1,024 channel 3D arrays) and microchips were fabricated by the foundries that will be used in this effort. These systems have been validated in vivo. In Y1, nanoprobe layer modules will be fabricated with 1,024 channels, and will be stackable into composite 3D systems with 10,240 full time/full bandwidth channels. In Y2 nanoprobe layer modules with 8,192 channels will be mass produced; these will be stackable to configure dense, composite 3D systems with ~100,000 full time/full bandwidth channels. These first two production runs enable systems for electrophysiological stimulation, recording, and neurochemical sensing. A third production run will integrate optogenetic stimulation with proximal multisite electrophysiological recording. These hybrid nanoprobes will contain 512 e-pixels for optogenetic stimulation and 512 proximal recording electrodes. This new technology will have lasting impact by incorporating diverse needs of the community at the outset. Using these electrophysiological, neurochemical, and optogenetic probes, eight enthusiastic ?alpha adopters? will investigate cortical and subcortical circuitry underlying movement and mood disorders such as Parkinson's disease in rat models (Gradinaru Lab); the behavioral and computational roles of cortical layers and circuits in the mouse whisker system (Bruno Lab), visual systems in the mouse (Yuste Lab) and primates (Tolias Lab); speech representations in human patients (Yvert Lab); the role of sleep in memory consolidation (Laurent Lab); coupling between neuronal activity and energy supply (Magistretti Lab); and the thirst nucleus of the mouse hypothalamus (Oka Lab). These users will provide direct feedback to enable probe refinement early in the effort. Interested ?beta? end-users, beyond these alpha adopters, will be recruited through solicitations in our publications, postings on our website, short talks at neuroscience conferences and by directly contact.